A cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e., a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate a specific tyrosine residue in proteins and hence to influence cell proliferation. Tyrosine kinases may be classified as growth factor receptor (e.g. EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. Such kinases may be aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancers such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. Aberrant erbB2 activity has been implicated in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers. Studies indicate that epidermal growth factor receptor (EGFR) is mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Thus, inhibitors of receptor tyrosine kinases may be useful as selective inhibitors of the growth of mammalian cancer cells.
EGFR inhibitors may be useful in the treatment of pancreatitis and kidney disease (such as proliferative glomerulonephritis and diabetes-induced renal disease), and may reduce successful blastocyte implantation and therefore may be useful as a contraceptive. See PCT international application publication number WO 95/19970 (published Jul. 27, 1995), hereby incorporated by reference in its entirety.
Polypeptide growth factors, such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995), hereby incorporated by reference in its entirety. Agents that are capable of binding to or modulating the KDR/FLK-1 receptor may be used to treat disorders related to vasculogenesis or angiogenesis, such as diabetes, diabetic retinopathy, age related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
Examples of compounds and methods that reportedly can be used to treat hyperproliferative diseases are disclosed in the following patents and applications: U.S. Pat. Nos. 6,534,524, 6,531,491 and 6,071,935; PCT international patent application publication nos. WO 00/38665 (published Jul. 6, 2001), WO 97/49688 (published Dec. 31, 1997), WO 98/23613 (published Jun. 4, 1998), WO 96/30347 (published Oct. 3, 1996), WO 96/40142 (published Dec. 19, 1996), WO 97/13771 (published Apr. 17, 1997), WO 95/23141 (published Aug. 31, 1995), WO 03/006059 (published Jan. 23, 2003), WO 03/035047 (published May 1, 2003), WO 02/064170 (published Aug. 22, 2002), WO 02/41882 (published May 30, 2002), WO 02/30453 (published Apr. 18, 2002), WO 01/85796 (published Nov. 15, 2001), WO 01/74360 (published Oct. 11, 2001), WO 01/74296 (published Oct. 11, 2001), WO 01/70268 (published Sep. 27, 2001) and WO 98/51344 (published Nov. 19, 1998); and European patent publication number EP 1086705 (published Mar. 28, 2001). The foregoing patent and applications are each incorporated herein by reference in their entirety.